Folic acid derivatives are coenzymes for several critical single-carbon transfer reactions, including reactions in the biosynthesis of purines, thymidylate and methionine. Methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) catalyses the NADPH-linked reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for methylation of homocysteine to methionine.
Hereditary deficiency of MTHFR, an autosomal recessive disorder, is the most common inborn error of folic acid metabolism. A block in the production of methyltetrahydrofolate leads to elevated homocysteine with low to normal levels of methionine. Patients with severe deficiencies of MTHFR (0-20% activity in fibroblasts) can have variable phenotypes. Developmental delay, mental retardation, motor and gait abnormalities, peripheral neuropathy, seizures and psychiatric disturbances have been reported in this group, although at least one patient with severe MTHFR deficiency was asymptomatic. Pathologic changes in the severe form include the vascular changes that have been found in other conditions with elevated homocysteine, as well as reduced neurotransmitter and methionine levels in the CNS. A milder deficiency of MTHFR (35-50% activity) has been described in patients with coronary artery disease (see below). Genetic heterogeneity is likely, considering the diverse clinical features, the variable levels of enzyme activity, and the differential heat inactivation profiles of the reductase in patients' cells.
MTHFR isolated from porcine liver has been purified to homogeneity and has been found to be a homodimer of 77-kDa subunits. Partial proteolysis of the porcine peptide has revealed two spatially distinct domains: an N-terminal domain of 40 kDa and a C-terminal domain of 37 kDa. The latter domain contains the binding site for the allosteric regulator S-adenosylmethionine.
The cDNA for human MTHFR has been isolated and mapped, and mutations in the gene have been identified in MTHFR-deficient individuals (Goyette, et al., (1994) Nat. Genet., 7:195-200). International Patent Application No. PCT/IB00/00442 discloses nucleic acid probes for the MTHFR gene, methods of identifying mutations in the MTHFR gene of individuals with MTHFR deficiency and methods of treatment for individuals with MTHFR deficiency involving the provision of a functional MTHFR gene or protein. The application further teaches that the MTHFR deficiency may be associated with a disease, disorder or dysfunction including cancers such as neuroblastomas and colorectal carcinomas.
PCT/IB00/00442 also postulates about a method for treating a patient having a cancer by inhibiting MTHFR gene expression or by inhibiting the MTHFR protein. However, given the teaching therein, it remains uncertain whether such a method would be effective in the treatment of cancer especially in view of the demonstrated link between MTHFR deficiency and disease. PCT/IB00/00442 does not discuss how the treatment of a patient having a cancer by inhibiting MTHFR gene expression or the MTHFR protein could be implemented or what effect such inhibition may have on cancer cells. In fact, PCT/IB00/00442 appears to teach that reducing MTHFR activity in a subject will have a deleterious effect.
There remains, therefore, a need for a method of selectively targeting cancer cells. In particular for a method that provides specific inhibition of the growth of cancer cells.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. Publications referred to throughout the specification are hereby incorporated by reference in their entireties in this application.